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LncRNA-mediated DNA methylation: an emerging mechanism in cancer and beyond

A Correction to this article was published on 27 August 2022

This article has been updated

Abstract

DNA methylation is one of the most important epigenetic mechanisms to regulate gene expression, which is highly dynamic during development and specifically maintained in somatic cells. Aberrant DNA methylation patterns are strongly associated with human diseases including cancer. How are the cell-specific DNA methylation patterns established or disturbed is a pivotal question in developmental biology and cancer epigenetics. Currently, compelling evidence has emerged that long non-coding RNA (lncRNA) mediates DNA methylation in both physiological and pathological conditions. In this review, we provide an overview of the current understanding of lncRNA-mediated DNA methylation, with emphasis on the roles of this mechanism in cancer, which to the best of our knowledge, has not been systematically summarized. In addition, we also discuss the potential clinical applications of this mechanism in RNA-targeting drug development.

Background

DNA methylation is the methyl modification on the fifth carbon of cytosines (5-methylcytosine, 5mC) typically found in the context of symmetrical CpG dinucleotides in mammals [1, 2]. It is estimated that 70–80% of CpG sites in the mammalian genome are methylated [3], excluding specific regions called CpG islands (CGIs). CGIs are CpG-rich sequences of about 1 kilo-base (kb) in length that mostly exist in gene promoters [4]. Approximately 60% of human gene promoters contain CGIs [5].

DNA methylation is established by DNA methyltransferases (DNMTs). In the simplified but widely accepted ‘division of labor’ model, it is proposed that DNMT3A and DNMT3B are essential for de novo DNA methylation, while DNMT1 is for methylation maintenance during DNA replication [6]. Ten-eleven translocation (TET) family of enzymes (TET1, TET2, and TET3) oppose the actions of the DNMT family by oxidation of 5mC, followed by replication-dependent dilution or thymine DNA glycosylase (TDG)-dependent base excision repair, leading to active DNA demethylation [7,8,9].

Genome-scale analysis revealed distinct DNA methylation patterns across different cell types, developmental stages, and in response to different stimuli [3, 10, 11]. Aberrant DNA methylation pattern is associated with diseases, including cancer [12,13,14,15]. In cancer cells, whereas the general DNA methylation levels are reduced, the CGIs are hypermethylated in a cancer-specific manner [16, 17]. These observations raised a fundamental question: how does the cell type-specific DNA methylation pattern established across the genome? It is well-demonstrated that histone modification and chromosome remodeling [18], as well as transcriptional factors, play key roles in the regulation of DNA methylation genome-wide and in site-specific manner [19,20,21,22]. Studies in recent years have accumulated compelling evidence to suggest that long non-coding RNA (lncRNA) is another important regulator of DNA methylation, especially in cancer.

While less than 2% of the human genome encodes proteins, nearly three-quarters can be actively transcribed into non-coding RNAs [23], amongst the ones typically with length more than 200 nucleotides are cataloged as lncRNAs. According to a current statistical analysis, there are more than 173,112 annotated lncRNAs transcribed from 96,411 genomic loci [24]. It is demonstrated that lncRNAs play versatile roles in development and diseases including cancer [25,26,27]. In the nucleus, lncRNAs regulate chromatin remodeling and transcription; In the cytoplasm, lncRNAs regulate translation and mRNA turnover (reviewed in ref. [27]). There is accumulating evidence up to date showing that lncRNAs mediate DNA methylation via multiple manners, thereby regulating target gene expression in diverse physiological and pathological processes. In this review, we summarize our current understanding of lncRNA-mediated DNA methylation, with emphasis on the functions of this mechanism in cancer. The future direction and potential clinical application are also discussed.

LncRNAs recruit DNA methyltransferases

More than a decade ago, it was discovered that lncRNAs transcribed from the promoter of rRNA genes (rDNA) regulate DNA methylation and transcription of rDNA [28]. Later, it was demonstrated that this kind of lncRNA interacts with rDNA promoter and forms a DNA: RNA triplex, which is recognized by DNMT3B to epigenetically regulate rDNA expression [29, 30]. Although it is still unclear if this is a common model nowadays, a variety of lncRNAs have been reported to recruit DNMTs and regulate target gene expression, playing key roles in mesoderm commitment [31], muscle regeneration [32, 33], neural differentiation [34], adipogenesis [35], mental disorder [36], cardiovascular diseases [37,38,39,40], osteoarthritis [41], as well as types of cancer (Table 1).

Table 1 LncRNAs mediate DNA methylation in cancer

Using an optimized RIP-seq method, Merry et al. identified 148 lncRNAs interacting with DNMT1 in colon cancer cells [56], and the following investigation showed that one of these lncRNAs, DACOR1, could recruit DNMT1 and reprogram genome-wide DNA methylation [57]. Currently, a growing number of studies suggest that lncRNA might recruit DNMTs directly to specific targets (Fig. 1a), including both protein-coding genes [43, 44, 46,47,48,49,50, 54, 55, 58] and non-coding genes such as miRNA [42, 51, 88]. For instance, in esophageal cancer (EC), lncRNA ADAMTS9-AS2 was reported to recruit DNMT1/3 to CDH3 promoter, inhibiting the cancer cell proliferation, invasion, and migration [49]. Two other lncRNAs, HOTAIR and LINC01270 might recruit DNMTs to the promoters of MTHFR and GSTP1 respectively, leading to chemoresistance in EC [47, 48]. In lung adenocarcinoma (LUAD), lncRNA HAGLR was identified as a tumor suppressor by recruiting DNMT1 to the promoter of E2F1 to inhibit tumor growth [55]. A recent study revealed a more complex scenario, in which the authors identified two novel variants of lncRNA LINC00887, and showed that the short form variant suppressed Carbonic Anhydrase IX (CA9) by recruiting DNMT1 to its promoter, while the long-form variant activated CA9's transcription via interacting with HIF1α [45]. The two variants were supposed to differentially respond to hypoxia and oppositely control the progression of tongue squamous carcinoma [45].

Fig. 1
figure 1

LncRNA interacts with DNMTs/TETs. a. LncRNAs directly recruit DNMTs/ TETs. b. LncRNAs indirectly recruit DNMTs via EZH2/PHB2. c. LncRNAs indirectly recruit TETs via GADD45A. d. LncRNAs sequestrate DNMTs

Meanwhile, several groups also proposed that lncRNAs could recruit DNMT indirectly through the mediation of other factors (Fig. 1b). It was previously proposed that the polycomb group (PcG) protein EZH2 (Enhancer of Zeste homolog 2) interacts with DNMT and associates with DNMT activity [89]. Studies in recent years demonstrated in diverse cancers that lncRNAs might regulate DNA methylation of target genes via association with EZH2, promoting tumor growth [75, 77], metastasis [74, 76, 78] and radio-resistance [79]. Alternatively, EZH2 might regulate DNA methylation by the formation of H3K27me3 histone modification [73], while the molecular mechanism involved in H3K27me3-induced DNA methylation is unclear. Apart from histone modifier EZH2, two transcriptional regulators, NF-κB and PHB2 were also reported to interact with DNMT3A [80, 90]. LncRNA NKILA was identified as a suppressor of NF-κB by sequestering NF-κB in cytoplasm [91]. Upon proinflammatory stimuli, NF-κB is released from the sequestration and translocated into the nucleus (Fig. 2). DNMT3A is then recruited to the promoter of KLF4 by NF-κB, repressing KLF4 transcription by DNA methylation [90]. Another study by Wang et al. reported a lncRNA called Lnc34a, which could interact with Prohibitin 2 (PHB2) and then recruit DNMT3A to miR-34a promoter, silencing miR-34a expression and promoting colorectal cancer growth [80]. PHB2 is a multi-functional protein that can shuttle between nucleus and mitochondria [92]. Interestingly, the nuclear-encoded lncRNA MALAT1 was recently discovered to be transported into mitochondria and to regulate the methylation status of mitochondrial DNA in hepatocellular carcinoma [59], yet the detailed mechanism is unclear.

Fig. 2
figure 2

LncRNAs regulate DNMT activity via nucleocytoplasmic shuttling. LncRNA CCDC26 interacts with DNMT1 and promotes its localization from the cytosol to the nucleus. LncRNA NKILA sequesters NF-κB in the cytoplasm, which hinders NF-κB recruitment of DNMT3A in the nucleus

While most of the reported function of lncRNA recruitment of DNMT is to target DNMT to specific genomic sites or regions, recent work from Jones et al. proposed a different model, in which the lncRNA CCDC26 specifically interacts with DNMT1 and promote its localization from the cytosol to nucleus (Fig. 2), while removal of CCDC26 leads to genome-wide hypomethylation, increasing double-stranded DNA breaks and inducing cell death [93]. More investigation is needed to confirm if the interaction is direct and to reveal the detailed mechanisms.

LncRNAs recruit TET enzymes

TET (Ten-eleven Translocation)-mediated 5mC oxidation is responsible for the active erasure of DNA methylation [94]. Studies from recent years have revealed that a subset of lncRNAs has the potential to interact with TETs and regulate DNA methylation (Table 1).

In some cases, lncRNA directly interacts with TETs and recruits them to specific targets (Fig. 1a). It was demonstrated that lncRNA Oplr16 binds to the Oct4 promoter, orchestrating the promoter-enhancer loops and then interacts with TET2 by the 3' region of Oplr16 [95]. Similarly, Du et al. identified two motifs in lncRNA Platr10 that interact with Oct4 promoter and TET1 respectively, thus inducing TET1- mediated DNA demethylation at specific site [96]. A research by Zhou et al. suggested that lncRNA TETILA regulates TET2 subcellular localization and enzymatic activity by binding to the DSBH (double-stranded β-helix) domain of TET2 [97]. In acute myeloid leukemia, lncRNA MAGI2-AS3 recruits TET2 to LRIG1 promoter, inducing up-regulation of LRIG1 and inhibition of leukemic stem cell self-renewal [85]. Interestingly, using RNA reverse transcription-associated trap sequencing (RAT-seq) approach to profile genome-wide interaction targets for lncRNAs in mice, a recent study reported that lncRNA Peblr20 recruits TET2 to the enhancer of Pou5F1 and activates the enhancer-transcribed RNAs [98]. Whether a similar mechanism exists in humans especially in cancer development remains uninvestigated.

There is also evidence supporting an indirect model (Fig. 1c), in which lncRNAs recruit TET via GADD45A. It was first reported by Arab et al. that an antisense lncRNA from TCF21 gene locus termed TARID might recruit GADD45A (growth arrest and DNA-damage-inducible, alpha), and GADD45A then recruits TET to the promoter of its partner gene and induce its activation by DNA demethylation [99]. In the following work, the authors further showed that TARID forms an R-loop at the TCF21 promoter to recruit GADD45A [100]. It was speculated that lncRNA PCDHα-AS might function in a similar mechanism to recruit TET3 via GADD45A, driving stochastic promoter choice to establish a neuronal surface identity code for circuit assembly [101]. In colorectal cancer (CRC), lncRNA SATB2-AS1 directly recruits WDR5 and GADD45A, promoting SATB2 transcription by histone modification, as well as DNA demethylation [87], which inhibits cell metastasis and regulates the immune response in CRC. Recently, a database was created, with a comprehensive list of R-loops and their respective regulatory proteins [102], which might serve as a useful resource to identify novel lncRNAs with the potential to recruit GADD45A via formation of R-loops.

LncRNAs repel/ sequestrate DNA methyltransferases

While most of the current reports suggest the DNMT-recruiting role of lncRNAs, some lncRNAs are also shown to repel or sequestrate DNMT to negatively regulate DNA methylation (Fig. 1d and Table 1).

It was first reported by Di Ruscio et al. that a lncRNA arising from the CEBPA gene locus binds to DNMT1 and prevents CEBPA promoter methylation [103]. The lncRNA DBCCR1-003 was reported to function similarly to suppress DBCCR1 promoter methylation by sequestrating DNMT1 and eventually to inhibit cell growth in bladder cancer [69]. In non-small cell lung cancer, lncRNA TTTY15 interacts with DNMT3A and inhibits the binding of DNMT3A to TBX4 promoter, while the lower expression level of TTTY15 is associated with tumor metastasis [70]. In glioblastoma, lncRNA HOTAIRM1 was suggested to interact with several epigenetic factors including DNMT1/3A/3B to sequester them away from HOXA1 promoter [71]. In breast cancer, it was discovered that lncRNA 91H, which is transcribed from the antisense orientation of H19, promotes oncogenesis by masking methylation site on the H19 promoter, inducing the oncogenic H19 overexpression [72].

LncRNAs control SAM/ SAH level to regulate DNMT activity

DNMT catalyzes transmethylation reactions using S-adenosylmethionine (SAM) as the methyl group donor, yielding S-adenosylhomocysteine (SAH) as a by-product, which is also a strong feedback inhibitor of DNMT [6]. In mammals, SAM is biosynthesized by methionine adenosyltransferase (MAT) from ATP and methionine [104], while SAH is reversibly cleaved into adenosine and homocysteine by S-adenosylhomocysteine hydrolase (SAHH, also known as AdoHcy hydrolase, AHCY), which is essential to prevent accumulation of SAH [104], thereby relieving its inhibition to DNMT (Fig. 3).

Fig. 3
figure 3

LncRNAs control SAM/SAH level to regulate DNMT activity. S-adenosylhomocysteine (SAM) is biosynthesized by MAT (methionine adenosyltransferase) and converted to SAH (S-adenosylhomocysteine) by DNMTs. SAH is also a strong feedback inhibitor of DNMTs and it can be cleaved by S-adenosylhomocysteine hydrolase (SAHH). LncRNAs control SAM/SAH level by interacting with MAT or SAHH, and carcinogens such as benzo [a]pyrene (BaP) might enhance the interaction

It was proposed that lncRNA H19 binds to and inhibits SAHH, leading to genome-wide methylation changes at numerous gene loci [105]. Afterward, this mechanism was verified in embryonic hematopoietic stem cell development [106], odontogenic differentiation [107], metabolic abnormality [108] and neurodegenerative diseases [109]. In breast cancer, it was demonstrated that H19 inhibits SAHH, resulting in the accumulation of SAH, which restricts DNMT3B from methylating Beclin1 promoter and inducing the upregulation of Beclin1 and subsequently initiates autophagy, contributing to tamoxifen resistance [81]. Interestingly, the interaction of H19 and SAHH might be enhanced by Benzo [a]pyrene (BaP), which is a potent carcinogen, especially in lung cancer [84].

Other than the SAH level regulated by SAHH, the SAM level regulated by MAT is another factor affecting DNMT activity (Fig. 3). MAT has several homologs and isoenzymes, among which, MAT1A is mainly expressed in adulthood, serving as a marker for the normal differentiated liver. While MAT2A is a marker for rapid liver growth and dedifferentiation, which is transcriptionally induced in hepatocellular carcinoma (HCC) [104]. It was reported that the oncogenic lncRNA SNHG6 upregulates MAT2A expression as a competitive endogenous RNA (ceRNA) to sponge miR-1297, while down-regulates MAT1A translation by suppressing nucleocytoplasmic shuttling of MAT1A mRNA, thereby causing genome-wide hypomethylation and promoting HCC [83]. Recently, the same group of investigators identified a novel lncRNA named LINC00662 that was shown to decay MAT1A mRNA by RNA–RNA interactions and degrades SAHH protein by ubiquitination [82]. These studies revealed a pathway regulating the level of SAM/SAH to further control DNMT activity, with broad functions in cancer and other diseases.

LncRNAs regulate the expression of DNMTs/ TETs

There is compelling evidence showing that lncRNAs control the expression of DNMTs and TETs at diverse levels to regulate DNA methylation (Table 1 and Fig. 4). It was reported that lncRNAs promote or suppress DNMT expression, playing key roles in osteogenesis [110], macrophage polarization [111], as well as cell invasion in Kaposi's sarcoma [63] and chemoresistance in small cell lung cancer [67] and acute myeloid leukemia [60]. Several molecular mechanisms of lncRNA’s regulatory effect on DNMTs or TETs have been elucidated (Fig. 4).

Fig. 4
figure 4

LncRNAs regulate the expression of DNMTs/ TETs at diverse levels. Firstly, lncRNAs might regulate the transcription of DNMTs via interaction with EZH2 to form repressive chromatin; Secondly, lncRNAs can stabilize DNMTs mRNA by recruiting HuR or as a miRNA sponge; Thirdly, lncRNAs regulate DNMT on the protein level by promoting or inhibiting its ubiquitination

The first mechanism is to regulate the transcription, as demonstrated in malignant glioma, where lncRNA GAS5 directly interacts with EZH2 and stimulates the formation of polycomb repressive complex 2 (PRC2), thereby transcriptionally suppressing DNMT [62]. There is also a report suggesting that EZH2 is recruited by lncRNA HOTAIR to upregulate DNMT, while the mechanism is unclear [66].

The second mechanism is to regulate the stability of DNMT mRNA, where lncRNA functions as a mediator to upregulating DNMT by interaction with the stabilizing factor HuR [112], or as a ceRNA to sponge specific miRNA, thereby upregulating DNMT [61]. The latter mechanism was also discovered in TET regulation, where estradiol and progesterone upregulate lncRNA H19 to suppress miRNA Let-7 and stabilize TET3 mRNA, activating key fibroid-promoting genes in uterine leiomyomas [68]. LncRNA might also exert this effect via a more indirect manner, as demonstrated for LINC1281, which stabilizes the expression of Let-7 miRNA, thus down-regulating its targets DNMT3A/B [113].

The third mechanism is to regulate DNMT at the protein level. Current studies mainly focus on protein degradation by ubiquitination (Fig. 4). It was reported by several groups that lncRNAs serve as a protein-binding scaffold and induce ubiquitin-mediated DNMT protein degradation, epigenetically regulating target gene expression in obesity-mediated beta cell dysfunction [114], polycystic ovary syndrome [115] and hepatocellular carcinoma (HCC) [64]. The detailed mechanism involving the role of lncRNA in DNMT ubiquitination is largely unknown and warrant more deep investigation. In esophageal squamous cell carcinoma, a distinct model was proposed, in which, the lncRNA LUCAT1 binds DNMT1 to protect it from ubiquitination, while LUCAT1 knock-down promotes ubiquitination of DNMT1 through UHRF1 (Ubiquitin-Like PHD and RING Finger Domain-Containing Protein 1) [65]. However, it is well established that UHRF1 deposits dual mono- ubiquitination on the H3 histone tail and PCNA-associated factor 15 (PAF15) for direct DNMT1 recruitment and DNA methylation maintenance [116,117,118], while its roles in the mediation of DNMT1 ubiquitination need further validation and investigation.

Conclusions and discussions

Studies in recent years have revealed the multi-faceted role of lncRNA in regulating DNA methylation. Firstly, lncRNAs can recruit or repel DNA modifiers (DNMTs/ TETs) to specific gene targets (Fig. 1; Fig. 2); Secondly, lncRNAs can regulate DNMT activity by controlling the level of DNMT cofactor SAM/ SAH (Fig. 3); Lastly, lncRNAs can regulate the expression of DNMTs/ TETs per se at multiple levels (Fig. 4). All these mechanisms have been investigated in development and disease, with emphasized roles in cancer.

While most of the studies focused on the DNA methylation of the gene promoters, there is also a recent report highlighting the gene-body methylation mediated by a lncRNA by recruiting DNMT3A, which facilitates transcription of CTSG in dermatomyositic myoideum [119]. Whether this mechanism exists in cancer needs further investigation.

Although this review mainly discussed the lncRNA function in mediating DNA methylation, another two issues should be noted. The first is that lncRNAs are in turn regulated targets of DNA methylation [120,121,122,123]; The second is that lncRNAs also mediate other epigenetic alterations such as histone modification and chromosome remodeling [124,125,126,127,128,129,130,131]. These issues provide an additional layer of gene expression regulation to form complex crosstalk between lncRNA, transcriptional factors, and various epigenetic modifications. More elaborate investigations are warranted to reveal the common mechanisms.

Perspectives

The emerging roles of lncRNAs in cancer through the mediation of DNA methylation suggest novel applications in drug development. While there are currently no drugs targeting lncRNA based exactly on this mechanism, relevant studies shed light on this field (Fig. 5).

Fig. 5
figure 5

Potential therapeutic strategies for lncRNA targeting based on lncRNA- mediated DNA methylation. The middle panel shows the interaction between lncRNA and DNA methylation regulators, which could be specifically interrupted by small molecular compounds (right panel). Alternatively, the regulators could also be modulated by lncRNA mimics (left panel)

One direction is to design lncRNA mimics to regulate the activity of their target proteins, which was recently applied in treating a rare disease of phenylketonuria, where a lncRNA HULC was identified to interact with phenylalanine hydroxylase (PAH) and to modulate the enzymatic activities of PAH. In their work, the authors constructed a lncRNA mimic that rescues PAH enzymatic activity in HULC-deficient cells and mouse models, which showed the therapeutic potential for phenylketonuria [132].

Another direction is to design small molecules directly targeting lncRNA-protein interactions [133,134,135,136]. Based on the structural insight of the interaction between lncRNA HOTAIR and EZH2, Ren et al. conducted a high-throughput virtual screening and identified a compound that selectively interrupts the lncRNA-protein interaction and inhibits cancer cell invasion and migration [137].

Owing to the fast progress of RNA structural biology and screening technologies, as well as the in-depth mechanistic studies and drug delivery technologies, it is reasonable to expect that RNA-targeting will emerge as a growing therapeutic strategy for human disorders, especially cancer.

Availability of data and materials

Not applicable.

Change history

Abbreviations

lncRNA:

Long non-coding RNA

CGIs:

CpG islands

DNMTs:

DNA methyltransferases

TET:

Ten-eleven translocation

TDG:

Thymine DNA glycosylase

PcG:

Polycomb group

PRC2:

Polycomb repressive complex 2

EZH2:

Enhancer of Zeste homolog 2

GADD45A:

Growth arrest and DNA-damage-inducible alpha

SAM:

S-adenosylmethionine

SAH:

S-adenosylhomocysteine

MAT:

Methionine adenosyltransferase

SAHH:

S-adenosylhomocysteine hydrolase

ceRNA:

Competitive endogenous RNA

BC:

Breast cancer

OC:

Oral cancer

CML:

Chronic myeloid leukemia

TSCC:

Tongue squamous cell carcinoma

TNBC:

Triple-negative breast cancer

EC:

Esophageal cancer

PCa:

Prostate cancer

RC:

Renal carcinoma

GBC:

Gallbladder cancer

HCC:

Hepatocellular carcinoma

OSA:

Osteosarcoma

NSCLC:

Non-small cell lung cancer

LUAD:

Lung adenocarcinoma

CRC:

Colorectal cancer

GC:

Gastric cancer

AML:

Acute myeloid leukemia

LSCC:

Laryngeal squamous cell carcinoma

KS:

Kaposi’s sarcoma

ESCC:

Esophageal squamous cell carcinoma

SCLC:

Small-cell lung cancer

UL:

Uterine leiomyomas

GBM:

Glioblastoma multiforme

CS:

Chondrosarcoma

References

  1. Greenberg MVC, Bourc’his D. The diverse roles of DNA methylation in mammalian development and disease. Nat Rev Mol Cell Biol. 2019;20:590–607.

    Article  CAS  PubMed  Google Scholar 

  2. Suzuki MM, Bird A. DNA methylation landscapes: provocative insights from epigenomics. Nat Rev Genet. 2008;9:465–76.

    Article  CAS  PubMed  Google Scholar 

  3. Ziller MJ, Gu H, Muller F, Donaghey J, Tsai LT, Kohlbacher O, et al. Charting a dynamic DNA methylation landscape of the human genome. Nature. 2013;500:477–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Deaton AM, Bird A. CpG islands and the regulation of transcription. Genes Dev. 2011;25:1010–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Li E, Zhang Y. DNA methylation in mammals. Cold Spring Harb Perspect Biol. 2014;6:a019133.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Lyko F. The DNA methyltransferase family: a versatile toolkit for epigenetic regulation. Nat Rev Genet. 2018;19:81–92.

    Article  CAS  PubMed  Google Scholar 

  7. Wu X, Zhang Y. TET-mediated active DNA demethylation: mechanism, function and beyond. Nat Rev Genet. 2017;18:517–34.

    Article  CAS  PubMed  Google Scholar 

  8. Rasmussen KD, Helin K. Role of TET enzymes in DNA methylation, development, and cancer. Genes Dev. 2016;30:733–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Wu SC, Zhang Y. Active DNA demethylation: many roads lead to Rome. Nat Rev Mol Cell Biol. 2010;11:607–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Lister R, Pelizzola M, Dowen RH, Hawkins RD, Hon G, Tonti-Filippini J, et al. Human DNA methylomes at base resolution show widespread epigenomic differences. Nature. 2009;462:315–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Meissner A, Mikkelsen TS, Gu H, Wernig M, Hanna J, Sivachenko A, et al. Genome-scale DNA methylation maps of pluripotent and differentiated cells. Nature. 2008;454:766–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Zhao SG, Chen WS, Li H, Foye A, Zhang M, Sjostrom M, et al. The DNA methylation landscape of advanced prostate cancer. Nat Genet. 2020;52:778–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Phillips RE, Soshnev AA, Allis CD. Epigenomic Reprogramming as a Driver of Malignant Glioma. Cancer Cell. 2020;38:647–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Sina AA, Carrascosa LG, Liang Z, Grewal YS, Wardiana A, Shiddiky MJA, et al. Epigenetically reprogrammed methylation landscape drives the DNA self-assembly and serves as a universal cancer biomarker. Nat Commun. 2018;9:4915.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Reddington JP, Sproul D, Meehan RR. DNA methylation reprogramming in cancer: does it act by re-configuring the binding landscape of Polycomb repressive complexes? BioEssays. 2014;36:134–40.

    Article  CAS  PubMed  Google Scholar 

  16. Baylin SB, Jones PA. Epigenetic Determinants of Cancer. Cold Spring Harb Perspect Biol. 2016;8(9):a019505.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Nishiyama A, Nakanishi M. Navigating the DNA methylation landscape of cancer. Trends Genet. 2021;37:1012–27.

    Article  CAS  PubMed  Google Scholar 

  18. Du J, Johnson LM, Jacobsen SE, Patel DJ. DNA methylation pathways and their crosstalk with histone methylation. Nat Rev Mol Cell Biol. 2015;16:519–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Zhu H, Wang G, Qian J. Transcription factors as readers and effectors of DNA methylation. Nat Rev Genet. 2016;17:551–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Heberle E, Bardet AF. Sensitivity of transcription factors to DNA methylation. Essays Biochem. 2019;63:727–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Schubeler D. Function and information content of DNA methylation. Nature. 2015;517:321–6.

    Article  CAS  PubMed  Google Scholar 

  22. Blattler A, Farnham PJ. Cross-talk between site-specific transcription factors and DNA methylation states. J Biol Chem. 2013;288:34287–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Djebali S, Davis CA, Merkel A, Dobin A, Lassmann T, Mortazavi A, et al. Landscape of transcription in human cells. Nature. 2012;489:101–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Zhao L, Wang J, Li Y, Song T, Wu Y, Fang S, et al. NONCODEV6: an updated database dedicated to long non-coding RNA annotation in both animals and plants. Nucleic Acids Res. 2021;49:D165–71.

    Article  CAS  PubMed  Google Scholar 

  25. Huarte M. The emerging role of lncRNAs in cancer. Nat Med. 2015;21:1253–61.

    Article  CAS  PubMed  Google Scholar 

  26. Batista PJ, Chang HY. Long noncoding RNAs: cellular address codes in development and disease. Cell. 2013;152:1298–307.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Yao RW, Wang Y, Chen LL. Cellular functions of long noncoding RNAs. Nat Cell Biol. 2019;21:542–51.

    Article  CAS  PubMed  Google Scholar 

  28. Mayer C, Schmitz KM, Li J, Grummt I, Santoro R. Intergenic transcripts regulate the epigenetic state of rRNA genes. Mol Cell. 2006;22:351–61.

    Article  CAS  PubMed  Google Scholar 

  29. Bierhoff H, Schmitz K, Maass F, Ye J, Grummt I. Noncoding transcripts in sense and antisense orientation regulate the epigenetic state of ribosomal RNA genes. Cold Spring Harb Symp Quant Biol. 2010;75:357–64.

    Article  CAS  PubMed  Google Scholar 

  30. Schmitz KM, Mayer C, Postepska A, Grummt I. Interaction of noncoding RNA with the rDNA promoter mediates recruitment of DNMT3b and silencing of rRNA genes. Genes Dev. 2010;24:2264–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Frank S, Ahuja G, Bartsch D, Russ N, Yao W, Kuo JC, et al. yylncT Defines a Class of Divergently Transcribed lncRNAs and Safeguards the T-mediated Mesodermal Commitment of Human PSCs. Cell Stem Cell. 2019;24:318-27 e8.

    Article  CAS  PubMed  Google Scholar 

  32. Ponnusamy M, Liu F, Zhang YH, Li RB, Zhai M, Liu F, et al. Long Noncoding RNA CPR (Cardiomyocyte Proliferation Regulator) Regulates Cardiomyocyte Proliferation and Cardiac Repair. Circulation. 2019;139:2668–84.

    Article  CAS  PubMed  Google Scholar 

  33. Wang L, Zhao Y, Bao X, Zhu X, Kwok YK, Sun K, et al. LncRNA Dum interacts with Dnmts to regulate Dppa2 expression during myogenic differentiation and muscle regeneration. Cell Res. 2015;25:335–50.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Chalei V, Sansom SN, Kong L, Lee S, Montiel JF, Vance KW, et al. The long non-coding RNA Dali is an epigenetic regulator of neural differentiation. Elife. 2014;3:e04530.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Yi F, Zhang P, Wang Y, Xu Y, Zhang Z, Ma W, et al. Long non-coding RNA slincRAD functions in methylation regulation during the early stage of mouse adipogenesis. RNA Biol. 2019;16:1401–13.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Ni C, Jiang W, Wang Z, Wang Z, Zhang J, Zheng X, et al. LncRNA-AC006129.1 reactivates a SOCS3-mediated anti-inflammatory response through DNA methylation-mediated CIC downregulation in schizophrenia. Mol Psychiatry. 2020;26(8):4511–28.

    Article  PubMed  Google Scholar 

  37. Deng Y, Chen D, Gao F, Lv H, Zhang G, Sun X, et al. Silencing of Long Non-coding RNA GAS5 Suppresses Neuron Cell Apoptosis and Nerve Injury in Ischemic Stroke Through Inhibiting DNMT3B-Dependent MAP4K4 Methylation. Transl Stroke Res. 2020;11:950–66.

    Article  CAS  PubMed  Google Scholar 

  38. Xie Z, Wang Q, Hu S. Coordination of PRKCA/PRKCA-AS1 interplay facilitates DNA methyltransferase 1 recruitment on DNA methylation to affect protein kinase C alpha transcription in mitral valve of rheumatic heart disease. Bioengineered. 2021;12:5904–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Li H, Han S, Sun Q, Yao Y, Li S, Yuan C, et al. Long non-coding RNA CDKN2B-AS1 reduces inflammatory response and promotes cholesterol efflux in atherosclerosis by inhibiting ADAM10 expression. Aging (Albany NY). 2019;11:1695–715.

    Article  CAS  Google Scholar 

  40. Wang Y, Yang X, Jiang A, Wang W, Li J, Wen J. Methylation-dependent transcriptional repression of RUNX3 by KCNQ1OT1 regulates mouse cardiac microvascular endothelial cell viability and inflammatory response following myocardial infarction. FASEB J. 2019;33:13145–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Chen H, Yang S, Shao R. Long non-coding XIST raises methylation of TIMP-3 promoter to regulate collagen degradation in osteoarthritic chondrocytes after tibial plateau fracture. Arthritis Res Ther. 2019;21:271.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Wang Q, Liu J, You Z, Yin Y, Liu L, Kang Y, et al. LncRNA TINCR favors tumorigenesis via STAT3-TINCR-EGFR-feedback loop by recruiting DNMT1 and acting as a competing endogenous RNA in human breast cancer. Cell Death Dis. 2021;12:83.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Su SC, Yeh CM, Lin CW, Hsieh YH, Chuang CY, Tang CH, et al. A novel melatonin-regulated lncRNA suppresses TPA-induced oral cancer cell motility through replenishing PRUNE2 expression. J Pineal Res. 2021;71:e12760.

    Article  CAS  PubMed  Google Scholar 

  44. Song H, Chen L, Liu W, Xu X, Zhou Y, Zhu J, et al. Depleting long noncoding RNA HOTAIR attenuates chronic myelocytic leukemia progression by binding to DNA methyltransferase 1 and inhibiting PTEN gene promoter methylation. Cell Death Dis. 2021;12:440.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Shen T, Xia W, Min S, Yang Z, Cheng L, Wang W, et al. A pair of long intergenic non-coding RNA LINC00887 variants act antagonistically to control Carbonic Anhydrase IX transcription upon hypoxia in tongue squamous carcinoma progression. BMC Biol. 2021;19:192.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Shao G, Fan X, Zhang P, Liu X, Huang L, Ji S. Methylation-dependent MCM6 repression induced by LINC00472 inhibits triple-negative breast cancer metastasis by disturbing the MEK/ERK signaling pathway. Aging (Albany NY). 2021;13:4962–75.

    Article  CAS  Google Scholar 

  47. Li N, Zhao Z, Miao F, Cai S, Liu P, Yu Y, et al. Silencing of long non-coding RNA LINC01270 inhibits esophageal cancer progression and enhances chemosensitivity to 5-fluorouracil by mediating GSTP1methylation. Cancer Gene Ther. 2021;28:471–85.

    Article  CAS  PubMed  Google Scholar 

  48. Zhang S, Zheng F, Zhang L, Huang Z, Huang X, Pan Z, et al. LncRNA HOTAIR-mediated MTHFR methylation inhibits 5-fluorouracil sensitivity in esophageal cancer cells. J Exp Clin Cancer Res. 2020;39:131.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Liu D, Wu K, Yang Y, Zhu D, Zhang C, Zhao S. Long noncoding RNA ADAMTS9-AS2 suppresses the progression of esophageal cancer by mediating CDH3 promoter methylation. Mol Carcinog. 2020;59:32–44.

    Article  CAS  PubMed  Google Scholar 

  50. Li Y, Luo Q, Li Z, Wang Y, Zhu C, Li T, et al. Long Non-coding RNA IRAIN Inhibits VEGFA Expression via Enhancing Its DNA Methylation Leading to Tumor Suppression in Renal Carcinoma. Front Oncol. 2020;10:1082.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Jin L, Cai Q, Wang S, Wang S, Wang J, Quan Z. Long noncoding RNA PVT1 promoted gallbladder cancer proliferation by epigenetically suppressing miR-18b-5p via DNA methylation. Cell Death Dis. 2020;11:871.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Wang W, Chen G, Wang B, Yuan Z, Liu G, Niu B, et al. Long non-coding RNA BZRAP1-AS1 silencing suppresses tumor angiogenesis in hepatocellular carcinoma by mediating THBS1 methylation. J Transl Med. 2019;17:421.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Miao H, Wang L, Zhan H, Dai J, Chang Y, Wu F, et al. A long noncoding RNA distributed in both nucleus and cytoplasm operates in the PYCARD-regulated apoptosis by coordinating the epigenetic and translational regulation. PLoS Genet. 2019;15:e1008144.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Kang X, Kong F, Huang K, Li L, Li Z, Wang X, et al. LncRNA MIR210HG promotes proliferation and invasion of non-small cell lung cancer by upregulating methylation of CACNA2D2 promoter via binding to DNMT1. Onco Targets Ther. 2019;12:3779–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Guo X, Chen Z, Zhao L, Cheng D, Song W, Zhang X. Long non-coding RNA-HAGLR suppressed tumor growth of lung adenocarcinoma through epigenetically silencing E2F1. Exp Cell Res. 2019;382:111461.

    Article  CAS  PubMed  Google Scholar 

  56. Merry CR, Forrest ME, Sabers JN, Beard L, Gao XH, Hatzoglou M, et al. DNMT1-associated long non-coding RNAs regulate global gene expression and DNA methylation in colon cancer. Hum Mol Genet. 2015;24:6240–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Somasundaram S, Forrest ME, Moinova H, Cohen A, Varadan V, LaFramboise T, et al. The DNMT1-associated lincRNA DACOR1 reprograms genome-wide DNA methylation in colon cancer. Clin Epigenetics. 2018;10:127.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Xin L, Lu H, Liu C, Zeng F, Yuan YW, Wu Y, et al. Methionine deficiency promoted mitophagy via lncRNA PVT1-mediated promoter demethylation of BNIP3 in gastric cancer. Int J Biochem Cell Biol. 2021;141:106100.

    Article  CAS  PubMed  Google Scholar 

  59. Zhao Y, Zhou L, Li H, Sun T, Wen X, Li X, et al. Nuclear-Encoded lncRNA MALAT1 Epigenetically Controls Metabolic Reprogramming in HCC Cells through the Mitophagy Pathway. Mol Ther Nucleic Acids. 2021;23:264–76.

    Article  CAS  PubMed  Google Scholar 

  60. Zhou W, Xu S, Chen X, Wang C. HOTAIR suppresses PTEN via DNMT3b and confers drug resistance in acute myeloid leukemia. Hematology. 2021;26:170–8.

    Article  CAS  PubMed  Google Scholar 

  61. Wang X, Yu B, Jin Q, Zhang J, Yan B, Yang L, et al. Regulation of laryngeal squamous cell cancer progression by the lncRNA RP11–159K7.2/miR-206/DNMT3A axis. J Cell Mol Med. 2020;24:6781–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Jin C, Zhao J, Zhang ZP, Wu M, Li J, Xiao GL, et al. Long non-coding RNA GAS5, by up-regulating PRC2 and targeting the promoter methylation of miR-424, suppresses multiple malignant phenotypes of glioma. J Neurooncol. 2020;148:529–43.

    Article  CAS  PubMed  Google Scholar 

  63. Li W, Wang Q, Feng Q, Wang F, Yan Q, Gao SJ, et al. Oncogenic KSHV-encoded interferon regulatory factor upregulates HMGB2 and CMPK1 expression to promote cell invasion by disrupting a complex lncRNA-OIP5-AS1/miR-218–5p network. PLoS Pathog. 2019;15:e1007578.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Xu X, Lou Y, Tang J, Teng Y, Zhang Z, Yin Y, et al. The long non-coding RNA Linc-GALH promotes hepatocellular carcinoma metastasis via epigenetically regulating Gankyrin. Cell Death Dis. 2019;10:86.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Yoon JH, You BH, Park CH, Kim YJ, Nam JW, Lee SK. The long noncoding RNA LUCAT1 promotes tumorigenesis by controlling ubiquitination and stability of DNA methyltransferase 1 in esophageal squamous cell carcinoma. Cancer Lett. 2018;417:47–57.

    Article  CAS  PubMed  Google Scholar 

  66. Cheng D, Deng J, Zhang B, He X, Meng Z, Li G, et al. LncRNA HOTAIR epigenetically suppresses miR-122 expression in hepatocellular carcinoma via DNA methylation. EBioMedicine. 2018;36:159–70.

    Article  PubMed  PubMed Central  Google Scholar 

  67. Fang S, Gao H, Tong Y, Yang J, Tang R, Niu Y, et al. Long noncoding RNA-HOTAIR affects chemoresistance by regulating HOXA1 methylation in small cell lung cancer cells. Lab Invest. 2016;96:60–8.

    Article  CAS  PubMed  Google Scholar 

  68. Cao T, Jiang Y, Wang Z, Zhang N, Al-Hendy A, Mamillapalli R, et al. H19 lncRNA identified as a master regulator of genes that drive uterine leiomyomas. Oncogene. 2019;38:5356–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Qi D, Li J, Que B, Su J, Li M, Zhang C, et al. Long non-coding RNA DBCCR1-003 regulate the expression of DBCCR1 via DNMT1 in bladder cancer. Cancer Cell Int. 2016;16:81.

    Article  PubMed  PubMed Central  Google Scholar 

  70. Lai IL, Chang YS, Chan WL, Lee YT, Yen JC, Yang CA, et al. Male-Specific Long Noncoding RNA TTTY15 Inhibits Non-Small Cell Lung Cancer Proliferation and Metastasis via TBX4. Int J Mol Sci. 2019;20(14):3473.

    Article  CAS  PubMed Central  Google Scholar 

  71. Li Q, Dong C, Cui J, Wang Y, Hong X. Over-expressed lncRNA HOTAIRM1 promotes tumor growth and invasion through up-regulating HOXA1 and sequestering G9a/EZH2/Dnmts away from the HOXA1 gene in glioblastoma multiforme. J Exp Clin Cancer Res. 2018;37:265.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Vennin C, Spruyt N, Robin YM, Chassat T, Le Bourhis X, Adriaenssens E. The long non-coding RNA 91H increases aggressive phenotype of breast cancer cells and up-regulates H19/IGF2 expression through epigenetic modifications. Cancer Lett. 2017;385:198–206.

    Article  CAS  PubMed  Google Scholar 

  73. Fang S, Shen Y, Chen B, Wu Y, Jia L, Li Y, et al. H3K27me3 induces multidrug resistance in small cell lung cancer by affecting HOXA1 DNA methylation via regulation of the lncRNA HOTAIR. Ann Transl Med. 2018;6:440.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Xuan Y, Wang Y. Long non-coding RNA SNHG3 promotes progression of gastric cancer by regulating neighboring MED18 gene methylation. Cell Death Dis. 2019;10:694.

    Article  PubMed  PubMed Central  Google Scholar 

  75. Xiong Y, Kuang W, Lu S, Guo H, Wu M, Ye M, et al. Long noncoding RNA HOXB13-AS1 regulates HOXB13 gene methylation by interacting with EZH2 in glioma. Cancer Med. 2018;7:4718–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Zhang C, Wang L, Jin C, Zhou J, Peng C, Wang Y, et al. Long non-coding RNA Lnc-LALC facilitates colorectal cancer liver metastasis via epigenetically silencing LZTS1. Cell Death Dis. 2021;12:224.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Bao X, Ren T, Huang Y, Sun K, Wang S, Liu K, et al. Knockdown of long non-coding RNA HOTAIR increases miR-454–3p by targeting Stat3 and Atg12 to inhibit chondrosarcoma growth. Cell Death Dis. 2017;8:e2605.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Sui CJ, Zhou YM, Shen WF, Dai BH, Lu JJ, Zhang MF, et al. Long noncoding RNA GIHCG promotes hepatocellular carcinoma progression through epigenetically regulating miR-200b/a/429. J Mol Med (Berl). 2016;94:1281–96.

    Article  CAS  Google Scholar 

  79. Liu F, Huang W, Hong J, Cai C, Zhang W, Zhang J, et al. Long noncoding RNA LINC00630 promotes radio-resistance by regulating BEX1 gene methylation in colorectal cancer cells. IUBMB Life. 2020;72:1404–14.

    Article  CAS  PubMed  Google Scholar 

  80. Wang L, Bu P, Ai Y, Srinivasan T, Chen HJ, Xiang K, et al. A long non-coding RNA targets microRNA miR-34a to regulate colon cancer stem cell asymmetric division. Elife. 2016;5:e14620.

    Article  PubMed  PubMed Central  Google Scholar 

  81. Wang J, Xie S, Yang J, Xiong H, Jia Y, Zhou Y, et al. The long noncoding RNA H19 promotes tamoxifen resistance in breast cancer via autophagy. J Hematol Oncol. 2019;12:81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Guo T, Gong C, Wu P, Battaglia-Hsu SF, Feng J, Liu P, et al. LINC00662 promotes hepatocellular carcinoma progression via altering genomic methylation profiles. Cell Death Differ. 2020;27:2191–205.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Guo T, Wang H, Liu P, Xiao Y, Wu P, Wang Y, et al. SNHG6 Acts as a Genome-Wide Hypomethylation Trigger via Coupling of miR-1297-Mediated S-Adenosylmethionine-Dependent Positive Feedback Loops. Cancer Res. 2018;78:3849–64.

    Article  CAS  PubMed  Google Scholar 

  84. Fu Y, Wang W, Li X, Liu Y, Niu Y, Zhang B, et al. LncRNA H19 interacts with S-adenosylhomocysteine hydrolase to regulate LINE-1 Methylation in human lung-derived cells exposed to Benzo[a]pyrene. Chemosphere. 2018;207:84–90.

    Article  CAS  PubMed  Google Scholar 

  85. Chen L, Fan X, Zhu J, Chen X, Liu Y, Zhou H. LncRNA MAGI2-AS3 inhibits the self-renewal of leukaemic stem cells by promoting TET2-dependent DNA demethylation of the LRIG1 promoter in acute myeloid leukaemia. RNA Biol. 2020;17:784–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Wang B, Zhao L, Chi W, Cao H, Cui W, Meng W. Aberrant methylation-mediated downregulation of lncRNA SSTR5-AS1 promotes progression and metastasis of laryngeal squamous cell carcinoma. Epigenetics Chromatin. 2019;12:35.

    Article  PubMed  PubMed Central  Google Scholar 

  87. Xu M, Xu X, Pan B, Chen X, Lin K, Zeng K, et al. LncRNA SATB2-AS1 inhibits tumor metastasis and affects the tumor immune cell microenvironment in colorectal cancer by regulating SATB2. Mol Cancer. 2019;18:135.

    Article  PubMed  PubMed Central  Google Scholar 

  88. Hu S, Yao Y, Hu X, Zhu Y. LncRNA DCST1-AS1 downregulates miR-29b through methylation in glioblastoma (GBM) to promote cancer cell proliferation. Clin Transl Oncol. 2020;22:2230–5.

    Article  CAS  PubMed  Google Scholar 

  89. Vire E, Brenner C, Deplus R, Blanchon L, Fraga M, Didelot C, et al. The Polycomb group protein EZH2 directly controls DNA methylation. Nature. 2006;439:871–4.

    Article  CAS  PubMed  Google Scholar 

  90. Zhu X, Du J, Yu J, Guo R, Feng Y, Qiao L, et al. LncRNA NKILA regulates endothelium inflammation by controlling a NF-kappaB/KLF4 positive feedback loop. J Mol Cell Cardiol. 2019;126:60–9.

    Article  CAS  PubMed  Google Scholar 

  91. Liu B, Sun L, Liu Q, Gong C, Yao Y, Lv X, et al. A cytoplasmic NF-kappaB interacting long noncoding RNA blocks IkappaB phosphorylation and suppresses breast cancer metastasis. Cancer Cell. 2015;27:370–81.

    Article  CAS  PubMed  Google Scholar 

  92. Artal-Sanz M, Tavernarakis N. Prohibitin and mitochondrial biology. Trends Endocrinol Metab. 2009;20:394–401.

    Article  CAS  PubMed  Google Scholar 

  93. Jones R, Wijesinghe S, Wilson C, Halsall J, Liloglou T, Kanhere A. A long intergenic non-coding RNA regulates nuclear localization of DNA methyl transferase-1. iScience. 2021;24:102273.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Wu H, Zhang Y. Reversing DNA methylation: mechanisms, genomics, and biological functions. Cell. 2014;156:45–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Jia L, Wang Y, Wang C, Du Z, Zhang S, Wen X, et al. Oplr16 serves as a novel chromatin factor to control stem cell fate by modulating pluripotency-specific chromosomal looping and TET2-mediated DNA demethylation. Nucleic Acids Res. 2020;48:3935–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Du Z, Wen X, Wang Y, Jia L, Zhang S, Liu Y, et al. Chromatin lncRNA Platr10 controls stem cell pluripotency by coordinating an intrachromosomal regulatory network. Genome Biol. 2021;22:233.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Zhou L, Ren M, Zeng T, Wang W, Wang X, Hu M, et al. TET2-interacting long noncoding RNA promotes active DNA demethylation of the MMP-9 promoter in diabetic wound healing. Cell Death Dis. 2019;10:813.

    Article  PubMed  PubMed Central  Google Scholar 

  98. Wang C, Jia L, Wang Y, Du Z, Zhou L, Wen X, et al. Genome-wide interaction target profiling reveals a novel Peblr20-eRNA activation pathway to control stem cell pluripotency. Theranostics. 2020;10:353–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Arab K, Park YJ, Lindroth AM, Schafer A, Oakes C, Weichenhan D, et al. Long noncoding RNA TARID directs demethylation and activation of the tumor suppressor TCF21 via GADD45A. Mol Cell. 2014;55:604–14.

    Article  CAS  PubMed  Google Scholar 

  100. Arab K, Karaulanov E, Musheev M, Trnka P, Schafer A, Grummt I, et al. GADD45A binds R-loops and recruits TET1 to CpG island promoters. Nat Genet. 2019;51:217–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Canzio D, Nwakeze CL, Horta A, Rajkumar SM, Coffey EL, Duffy EE, et al. Antisense lncRNA Transcription Mediates DNA Demethylation to Drive Stochastic Protocadherin alpha Promoter Choice. Cell. 2019;177:639-53 e15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Lin R, Zhong X, Zhou Y, Geng H, Hu Q, Huang Z, et al. R-loopBase: a knowledgebase for genome-wide R-loop formation and regulation. Nucleic Acids Res. 2021;50(D1):D303–15.

    Article  PubMed Central  Google Scholar 

  103. Di Ruscio A, Ebralidze AK, Benoukraf T, Amabile G, Goff LA, Terragni J, et al. DNMT1-interacting RNAs block gene-specific DNA methylation. Nature. 2013;503:371–6.

    Article  PubMed  PubMed Central  Google Scholar 

  104. Lu SC, Mato JM. S-adenosylmethionine in liver health, injury, and cancer. Physiol Rev. 2012;92:1515–42.

    Article  CAS  PubMed  Google Scholar 

  105. Zhou J, Yang L, Zhong T, Mueller M, Men Y, Zhang N, et al. H19 lncRNA alters DNA methylation genome wide by regulating S-adenosylhomocysteine hydrolase. Nat Commun. 2015;6:10221.

    Article  CAS  PubMed  Google Scholar 

  106. Zhou J, Xu J, Zhang L, Liu S, Ma Y, Wen X, et al. Combined Single-Cell Profiling of lncRNAs and Functional Screening Reveals that H19 Is Pivotal for Embryonic Hematopoietic Stem Cell Development. Cell Stem Cell. 2019;24:285-98 e5.

    Article  CAS  PubMed  Google Scholar 

  107. Zeng L, Sun S, Han D, Liu Y, Liu H, Feng H, et al. Long non-coding RNA H19/SAHH axis epigenetically regulates odontogenic differentiation of human dental pulp stem cells. Cell Signal. 2018;52:65–73.

    Article  CAS  PubMed  Google Scholar 

  108. Deng J, Mueller M, Geng T, Shen Y, Liu Y, Hou P, et al. H19 lncRNA alters methylation and expression of Hnf4alpha in the liver of metformin-exposed fetuses. Cell Death Dis. 2017;8:e3175.

    Article  PubMed  PubMed Central  Google Scholar 

  109. Spinelli M, Boucard C, Ornaghi S, Schoeberlein A, Irene K, Coman D, et al. Preimplantation factor modulates oligodendrocytes by H19-induced demethylation of NCOR2. JCI Insight. 2021;6(20):e132335.

    Article  PubMed  PubMed Central  Google Scholar 

  110. Chen Z, Zheng J, Hong H, Chen D, Deng L, Zhang X, et al. lncRNA HOTAIRM1 promotes osteogenesis of hDFSCs by epigenetically regulating HOXA2 via DNMT1 in vitro. J Cell Physiol. 2020;235:8507–19.

    Article  CAS  PubMed  Google Scholar 

  111. Li X, Zhang Y, Pei W, Zhang M, Yang H, Zhong M, et al. LncRNA Dnmt3aos regulates Dnmt3a expression leading to aberrant DNA methylation in macrophage polarization. FASEB J. 2020;34:5077–91.

    Article  CAS  PubMed  Google Scholar 

  112. Peng WX, Koirala P, Zhang W, Ni C, Wang Z, Yang L, et al. lncRNA RMST Enhances DNMT3 Expression through Interaction with HuR. Mol Ther. 2020;28:9–18.

    Article  CAS  PubMed  Google Scholar 

  113. Li MA, Amaral PP, Cheung P, Bergmann JH, Kinoshita M, Kalkan T, et al. A lncRNA fine tunes the dynamics of a cell state transition involving Lin28, let-7 and de novo DNA methylation. Elife. 2017;6:e23468.

    Article  PubMed  PubMed Central  Google Scholar 

  114. Zhang FF, Liu YH, Wang DW, Liu TS, Yang Y, Guo JM, et al. Obesity-induced reduced expression of the lncRNA ROIT impairs insulin transcription by downregulation of Nkx6.1 methylation. Diabetologia. 2020;63:811–24.

    Article  CAS  PubMed  Google Scholar 

  115. Geng X, Zhao J, Huang J, Li S, Chu W, Wang WS, et al. lnc-MAP3K13-7:1 Inhibits Ovarian GC Proliferation in PCOS via DNMT1 Downregulation-Mediated CDKN1A Promoter Hypomethylation. Mol Ther. 2021;29:1279–93.

    Article  CAS  PubMed  Google Scholar 

  116. Nishiyama A, Mulholland CB, Bultmann S, Kori S, Endo A, Saeki Y, et al. Two distinct modes of DNMT1 recruitment ensure stable maintenance DNA methylation. Nat Commun. 2020;11:1222.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Petryk N, Bultmann S, Bartke T, Defossez PA. Staying true to yourself: mechanisms of DNA methylation maintenance in mammals. Nucleic Acids Res. 2021;49:3020–32.

    Article  CAS  PubMed  Google Scholar 

  118. Qin W, Wolf P, Liu N, Link S, Smets M, La Mastra F, et al. DNA methylation requires a DNMT1 ubiquitin interacting motif (UIM) and histone ubiquitination. Cell Res. 2015;25:911–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Liang Y, Peng Y. Gene body methylation facilitates the transcription of CTSG via antisense lncRNA AL136018.1 in dermatomyositic myoideum. Cell Biol Int. 2021;45:456–62.

    Article  CAS  PubMed  Google Scholar 

  120. Hadji F, Boulanger MC, Guay SP, Gaudreault N, Amellah S, Mkannez G, et al. Altered DNA Methylation of Long Noncoding RNA H19 in Calcific Aortic Valve Disease Promotes Mineralization by Silencing NOTCH1. Circulation. 2016;134:1848–62.

    Article  CAS  PubMed  Google Scholar 

  121. Yang Z, Xu F, Wang H, Teschendorff AE, Xie F, He Y. Pan-cancer characterization of long non-coding RNA and DNA methylation mediated transcriptional dysregulation. EBioMedicine. 2021;68:103399.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Lu C, Wei Y, Wang X, Zhang Z, Yin J, Li W, et al. DNA-methylation-mediated activating of lncRNA SNHG12 promotes temozolomide resistance in glioblastoma. Mol Cancer. 2020;19:28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Morenos L, Chatterton Z, Ng JL, Halemba MS, Parkinson-Bates M, Mechinaud F, et al. Hypermethylation and down-regulation of DLEU2 in paediatric acute myeloid leukaemia independent of embedded tumour suppressor miR-15a/16-1. Mol Cancer. 2014;13:123.

    Article  PubMed  PubMed Central  Google Scholar 

  124. Tsai MC, Manor O, Wan Y, Mosammaparast N, Wang JK, Lan F, et al. Long noncoding RNA as modular scaffold of histone modification complexes. Science. 2010;329:689–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Fang H, Bonora G, Lewandowski JP, Thakur J, Filippova GN, Henikoff S, et al. Trans- and cis-acting effects of Firre on epigenetic features of the inactive X chromosome. Nat Commun. 2020;11:6053.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Liu YW, Xia R, Lu K, Xie M, Yang F, Sun M, et al. LincRNAFEZF1-AS1 represses p21 expression to promote gastric cancer proliferation through LSD1-Mediated H3K4me2 demethylation. Mol Cancer. 2017;16:39.

    Article  PubMed  PubMed Central  Google Scholar 

  127. Huang MD, Chen WM, Qi FZ, Sun M, Xu TP, Ma P, et al. Long non-coding RNA TUG1 is up-regulated in hepatocellular carcinoma and promotes cell growth and apoptosis by epigenetically silencing of KLF2. Mol Cancer. 2015;14:165.

    Article  PubMed  PubMed Central  Google Scholar 

  128. Hanly DJ, Esteller M, Berdasco M. Interplay between long non-coding RNAs and epigenetic machinery: emerging targets in cancer? Philos Trans R Soc Lond B Biol Sci. 2018;373(1748):20170074.

    Article  PubMed  PubMed Central  Google Scholar 

  129. Wang KC, Yang YW, Liu B, Sanyal A, Corces-Zimmerman R, Chen Y, et al. A long noncoding RNA maintains active chromatin to coordinate homeotic gene expression. Nature. 2011;472:120–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Gu P, Chen X, Xie R, Han J, Xie W, Wang B, et al. lncRNA HOXD-AS1 Regulates Proliferation and Chemo-Resistance of Castration-Resistant Prostate Cancer via Recruiting WDR5. Mol Ther. 2017;25:1959–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Xia M, Liu J, Liu S, Chen K, Lin H, Jiang M, et al. Ash1l and lnc-Smad3 coordinate Smad3 locus accessibility to modulate iTreg polarization and T cell autoimmunity. Nat Commun. 2017;8:15818.

    Article  PubMed  PubMed Central  Google Scholar 

  132. Li Y, Tan Z, Zhang Y, Zhang Z, Hu Q, Liang K, et al. A noncoding RNA modulator potentiates phenylalanine metabolism in mice. Science. 2021;373:662–73.

    Article  CAS  PubMed  Google Scholar 

  133. Warner KD, Hajdin CE, Weeks KM. Principles for targeting RNA with drug-like small molecules. Nat Rev Drug Discov. 2018;17:547–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Sztuba-Solinska J, Chavez-Calvillo G, Cline SE. Unveiling the druggable RNA targets and small molecule therapeutics. Bioorg Med Chem. 2019;27:2149–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Hargrove AE. Small molecule-RNA targeting: starting with the fundamentals. Chem Commun (Camb). 2020;56:14744–56.

    Article  CAS  Google Scholar 

  136. Disney MD, Angelbello AJ. Rational Design of Small Molecules Targeting Oncogenic Noncoding RNAs from Sequence. Acc Chem Res. 2016;49:2698–704.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Ren Y, Wang YF, Zhang J, Wang QX, Han L, Mei M, et al. Targeted design and identification of AC1NOD4Q to block activity of HOTAIR by abrogating the scaffold interaction with EZH2. Clin Epigenetics. 2019;11:29.

    Article  PubMed  PubMed Central  Google Scholar 

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Funding

This work was financially supported by the National Natural Science Foundation of China (32000426 and 31971335) to Huang W and Wang DO; the National Key R&D Program of China (2021YFC2009302) to Li H; Special Funds for Transformation and Upgrading of Industrial Informatization of Industry and Information Technology Department of Jiangsu in 2020 to Xiao W; Xingliao Talents Program (XLYC1802007) and Department of Education of Liaoning Province (1911520092) to Wang DO.

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W.H. and H.L. and Q.Y. retrieved literature; W.H. and H.L. wrote the manuscript and prepared the figures; W.X. and D.W. critically revised the manuscript. All authors have read and approved the final manuscript.

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Correspondence to Wanxu Huang or Wei Xiao.

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The original online version of this article was revised: an error was identified in five references--References 48, 53, 55, 61, and 63.

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Huang, W., Li, H., Yu, Q. et al. LncRNA-mediated DNA methylation: an emerging mechanism in cancer and beyond. J Exp Clin Cancer Res 41, 100 (2022). https://doi.org/10.1186/s13046-022-02319-z

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